Diabetic retinopathy (DR) is an ischemic retinopathy, which has also been described as an inflammatory disorder. DR and other ischemic retinopathies cause significant visual loss through blood-retinal barrier (BRB) breakdown and retinal neovascularization (NV). A number of molecules have been identified that are associated with ischemia and/or are pro-inflammatory and are implicated with the pathogenesis of DR. These molecules include vascular endothelial growth factor (VEGF) and its receptors, placental growth factor (PIGF), and tumor necrosis factor-a (TNFa). VEGF, PIGF, and TNFa are angiogenic and VEGF and TNFa are also pro-inflammatory. VEGF has been identified as a key molecule in mediating the adverse effects of ischemic retinopathies such as DR, retinopathy of prematurity, and branch and central retinal vein occlusions, but PIGF and TNFa have been shown to potentiate the angiogenic and vasopermeability activities of VEGF. Through the use of TNFa knockout mice and a variety of antagonists that operate through different signaling pathways, the roles of these molecules in the pathogenesis of ischemic retinopathies and the pathways involved may be determined. Interrupting the appropriate signaling pathway could impede the progression of DR and other ischemic retinopathies and antagonists of VEGF receptors. TNFa, PIGF, and PKC will be evaluated for this potential. A variety of molecules are associated with DR and other ischemic retinopathies, but due to the complexity of DR, it is unlikely that targeting a single molecule will effectively inhibit BRB breakdown leading to macular edema. If the molecules and pathways that are critical for the adverse effects of DR to develop are identified, they can be used as targets for its treatment. If multiple target molecules are identified, combination therapies can be devised to provide maximum therapeutic effectiveness while minimizing adverse effects.